Local Chemotherapy of Cerebral High-Grade Gliomas with Cisplatin-Loaded Polymer

A.F. Smeyanovich, Yu.G. Shanko, E.A. Korotkevich, S.V. Sheleg, E.A. Zhavrid,
Yu.N. Lukasheiko, I.M. Bychkovsky, T.L. Yukshtovich

Research Institute of Neurology, Neurosurgery and Physiotherapy of the Byelorussian Ministry of Public Health, Minsk, Byelorussia
Aleksandrov Research Institute of Oncology and Medical Radiology, Minsk, Byelorussia
Laboratory of Medicinal Preparations Based on Modified Polysaccharides (Research Institute of Physical-Chemical Problems of the Byelorussian State University), Minsk, Byelorussia

Summary

We have analyzed the results of treatment of 37 patients with cerebral high-grade gliomas (HGG). Multimodality treatment, carried out in 17 of them, consisted in resection of a tumor within the limits of intact tissue and implantation of a cisplatin-loaded polymer (CLP) into the operative wound walls (the preparation, used for implantation in one patient, included 20 polymer plates of 1.5x1.5 cm with a total dose of cisplatin, equal to 45 mg). It was followed by radiotherapy, applied to a bed of an ablated tumor (a total irradiation dose (TID) of 60 Gy). Patients of the control group (20) were treated by standard combined methods (analogous surgical intervention and radiotherapy with TID of 60 Gy, applied to a bed of a resected tumor).

The survival median in patients, subject to local chemotherapy with CLP, was 433 days. It was two times longer in comparison with standard combined treatment (214 days).

The multimodality treatment of cerebral HGG, employing local chemotherapy with CLP, was tolerated by patients satisfactorily; a psychoneurologic status and laboratory indices were indicative of absence of serious side effects.

High-grade gliomas (HGG) are a group of malignant cerebral tumors of neuroectodermal origin. According to the WHO classification [2], they include anaplastic gliomas (anaplastic astrocytomas, ependymomas, oligodendrogliomas) and multiform glioblastomas).

Today HGG treatment is one of the most urgent problems of neurosurgery and oncology. Despite use of practically all existing antineoplastic surgical and therapeutic methods in multimodality treatment of this disease, an average index of survival is, as a rule, not more than 12 months [15, 16, 28, 34].

HGG is a local process, taking into account biology of a tumor growth. It conditions possible wide use of local methods of antineoplastic treatment in this disease. One of the most prospective of them is local chemotherapy.

There are several reports both in home and foreign literature, describing clinical experience of applying solutions of various antineoplastic drugs for chemotherapy. However, obtained results are not very comforting [3-6, 19, 31, 36]. During the last years some researchers made attempts to use cytostatic drugs, loaded on dissolving polymers, for HGG chemotherapy [12-14, 25, 26].

Laboratory of Medicinal Preparations Based on Modified Polysaccharides (Research Institute of Physical-Chemical Problems of the Byelorussian State University) developed a new form of antineoplastic cisplatin, loaded on a home dissolving 6-carboxycellulose polymer, authorized for implantation into biological tissues of the human body on the territory of Byelorussia. Studies in vitro and in vivo showed its cytostatic effect, which was not lower than that of pure cisplatin. Besides, this form did not cause a marked toxic effect both on intact cerebral tissue just on the spot of its implantation and more remote areas [7, 8].

The goal of the present work

To study tolerance and to estimate results of treatment of patients with cerebral HGG, employing local chemotherapy with the cisplatin-loaded polymer (CLP).

Material and Methods

The cisplatin-loaded polymer is a mixture of cis-diaminedichlorplatinum (II) and 6-carboxycellulose in the following ratio (weight %):

The mixture of cis-diaminedichlorplatinum (II) and 6-carboxycellulose was received due to cellulose oxidation by nitrogen dioxide and a subsequent process of interaction of oxidized cellulose with cis-diaminedichlorplatinum (II) [1].

Cisplatin density on monocarboxycellulose was 1 mg/cm2 of the dissolving polymer.

CLP plates were sealed hermetically in a polyethylene-cellophane film and sterilized by g-rays in a dose of 25 000 Gy. A set, used for implantation into a bed of a malignant resected tumor in one patient (fig.1), included 20 polymer plates of 1.5x1.5 cm (total area and cisplatin dose equal to 45 cm2 and 45 mg respectively). Clinical trials of this drug were authorized by the Pharmacopoeia Committee of the Byelorussian Ministry of Public Health (N 01-03-09/2692).

The analysis of treatment of 37 patients with cerebral HGG was made. The main group was represented by 17 cases, who underwent multimodality treatment and local chemotherapy with CLP in 1998-2000. The control group included 20 patients, subject to standard combined treatment in 1990-1998.

There were 25 (68%) males and 12 (32%) females in main and control groups. An average age was 50.7±1.7 years.

Distribution of patients of these groups, dependent on a tumor's morphologic structure, is given in table 1.

A tumor stage in cases with HGG was determined on the basis of the TNM International Classification of CNS Supratentorial Tumors [9]. All the patients had the stage of pT2MoG3-4.

The main criteria of patients' selection were as follows:

  1. Possible removal of a cerebral tumor within the limits of intact tissue.
  2. Pathomorphologic data, confirming HGG presence.
  3. A preoperative state, estimated according to Karnofsky's scale as 50% and more [21].

Table 1

Distribution of Patients According to a Tumor's Morphologic Structure

A Histological Type of a Tumor

Main Group

Control Group

Total

 

Abs.

%

Abs.

%

Abs.

%

Glioblastomas

14

82

18

90

32

87

Anaplastic gliomas

3

18

2

10

5

13

Total

17

100

20

100

37

100

Each patient, participating in this study, or his guardians gave a signed consent to multimodality treatment, which included chemotherapy with CLP.

All the patients underwent thorough general (with mandatory estimation of renal function) and detailed neurologic examinations before an operation. Axial CT examination of the brain (Somatom ARC and Somatom CR, Siemens) was carried out after sutures removal and in 1, 3, 6, 9 and 12 months after operation.

All the cases were operated in the Neurosurgical Department of the Research Institute of Neurology, Neurosurgery and Physiotherapy of the Byelorussian Public Health Ministry. Malignant neoplasms were removed radically within the limits of intact cerebral tissue.

A surgical approach was calculated and planned (a place and size of a trephination window) on the basis of CT and/or MRI findings. Osteoplastic trephination of the skull was performed and dura mater was opened. If neoplasm spread to the brain convexital surface, then the cortex around it was coagulated and dissected. In subcortical localization of a tumor, encephalotomy through less eloquent gyruses was made. Taking into account an infiltrative growth of neoplasms, the latter were not exposed with spatulas, but enucleated with ultrasonic or vacuum aspirators. Removal of a central part and ensuring intermediate hemostatis were followed by resection of lateral segments of a tumor within the limits of visible intact cerebral tissue. Then final hemostatis was provided. A tumor bed was covered with CLP plates (fig.2), which were often soaked with sanies and adhered to cerebral tissue tightly. Dura mater was sutured or its plasty with a periosteal graft was performed. A bone fragment was removed in all cases with the purpose of decompression in case of a possible prolonged growth of a tumor. An operative wound was sutured layer-by-layer.

The patients were transferred to the Radiologic Department of the Aleksandrov Research Institute of Oncology and Medical Radiology in 2-3 weeks after operation. A course of radiotherapy was as follows: the first stage consisted in total irradiation of the brain (a single irradiation dose of 4 Gy, 5 fractions/week, a total irradiation dose of 20 Gy, which was isoequivalent to 30 Gy of conventional fractionation mode); the second stage took place immediately after the first one and included additional irradiation of a resected tumor bed in a mode of conventional fractionation up to TID, isoequivalent to 60 Gy. Not a single patient needed repeated cytoreductive intervention, caused by a tumor prolonged growth. It allowed to compare results of treatment.

A period of survival since the moment of operation was taken into account in estimation of treatment efficacy.

Оценка эффективности лечения включала продолжительность жизни больных с момента выполненной хирургической операции.

Cumulative survival of patients with HGG was calculated on the basis of the Kaplan-Meier method [20]. Mantel-Haenszel test (a logrank test) [30] was used for comparison of results.

Criteria of common toxicity of antineoplastic treatment, worked out by the US National Institute of Cancer, were used for scoring a degree, to which side and toxic effects of multimodality treatment, including local chemotherapy with CLP, were marked in patients with cerebral HGG.

Results and Discussion

Survival of patients is known to be the main criterion of efficacy of any method of antineoplastic treatment. In spite of use of the whole complex of antineoplastic treatment, average survival of patients with HGG does not exceed a year. Thus, it is impossible to use such indices as survival of 5 and even 2 years, as the majority of patients will die earlier. If treatment is capable to postpone a fatal outcome for at least a short period of time, it can be considered to be effective. This fact is of peculiar importance, because a state of cases with cerebral HGG can be satisfactory to this or that degree before a start of a tumor prolonged growth; some of them can even return to their previous place of work. That is why, estimation of direct results of multimodality treatment was carried out with taking into account both objective and subjective data.

The results of radical removal of a cerebral tumor with subsequent implantation of CLP were satisfactory in all the cases of the main group. Not a single patient developed brain edema, demanding intensive care, in a postoperative period.

There were no serious side and toxic effects of local chemotherapy with CLP during a course of radiation therapy. All psychoneurologic and somatic disorders, watched in the patients, did not exceed the first degree of toxic manifestations of treatment according to criteria of the US National Institute of Cancer. There were no pathologic changes in indices of laboratory tests during two months after CLP implantation.

CLP looked like a strip, covering a bed of a removed tumor, on CT images of the brain. Its rentgenologic density (Housefield's scale) varied from +60 up to +80 units (fig.3). According to CT findings, complete biological degradation of CLP was watched in 1.5-3 months after operation.

Description and results of treatment of patients with cerebral HGG, included into the main group, are given in table 2.

Table 2

Patients of the Main Group: Description and Results of Treatment

N

Patient

Sex

Age

A Histologic Type of a Tumor

A Relapse-Free Period

1.

Ya.

Male

33

Glioblastoma

162 days

2.

К.

Female

15

Glioblastoma

187 days

3.

А.

Male

22

Anaplastic astrocytoma

301 days

4.

B.

Male

62

Glioblastoma

156 days

5.

K.

Male

61

Glioblastoma

300 days

6.

G.

Male

61

Glioblastoma

257 days

7.

S.

Female

44

Glioblastoma

401 days

8.

A.

Female

65

Anaplastic astrocytoma

218 days

9.

T.

Male

44

Glioblastoma

422 days

10.

S.

Male

61

Glioblastoma

551 days

11.

S.

Male

19

Glioblastoma

513 days

12.

K.

Male

60

Glioblastoma

450 days

13.

T.

Female

46

Glioblastoma

406 days

14.

Sh.

Male

64

Glioblastoma

365 days

15.

N.

Female

37

Anaplastic astrocytoma

274 days

16.

A.

Female

65

Glioblastoma

128 days

17.

T.

Male

64

Glioblastoma

113 days

As for the control group, only one patient outlived the first year after operation. An average period of survival was 33.2±2.7 weeks; a survival median was equal to 214 days.

An average period of follow-up in the main group was 306.1±33.1 days. The first year after operation was outlived by 7 cases. A survival median was 433 days.

Problems of local chemotherapy of cerebral HGG with infusion of antineoplastic drugs (methotrexat, adriamicin, etc.) into a bed of a removed tumor were studied both by home and foreign neurosurgeons [10, 19, 37, 44]. However, such administration of cytostatic preparations was characterized by their marked diffusion into liquor of a subarachnoid space. On the one hand, it resulted in reduction of an antineoplastic effect; on the other hand, a response of the CNS to this treatment was rather severe and led leukoencephalopathy [31, 36, 37]. Thus, it became a cause of development of an original method of local chemotherapy with antineoplastic drugs, loaded on dissolving polymers and their programmed release into biological tissues [12-14, 27, 32, 42].

Fundamental research and clinical trials of antineoplastic drugs, possessing a prolonged effect and loaded on dissolving polymers, and their use for local interstitial chemotherapy of malignant cerebral tumors were carried out by Prof. Henry Brem, an American neurosurgeon, who is a world-famous and leading specialist in this field (Clinic of Neurosurgery of the John Hopkins University School of Medicine, Baltimore, USA) [13].

Brem H. et al. (1991) [12] used local chemotherapy with BCNU, immobilized on a biodegrading polymer (Polyanhydride), for treatment of 21 patients with recurrences of malignant cerebral gliomas; it was done at the I-II stage of clinical trials.

BCNU, immobilized on the above polymer, was implanted in the form of "waffle disks" with a diameter of 1.4 cm into a bed of a partially removed tumor. There were three groups of cases; they were implanted a cytostatic drug in a dose of 3.85 mg, 7.7 mg and 12.7 mg of BCNU/"waffle disk" respectively; a total dose varied from 31up to 102 mg. An average survival of patients, subject to chemotherapy, was 46 weeks since the moment of repeated surgical intervention. The authors revealed no toxic manifestations on the part of the hematopoietic system and internal organs. Some patients underwent subsequent interventions for removal of necrotic areas of a tumor.

According to data of the multi-center clinical study (27 medical centers of the USA, 222 patients with recurring cerebral HGG), carried out at the III stage of clinical trials of local chemotherapy with BCNU, a survival median of patients was 31 weeks. Six-month survival of cases, subject to local chemotherapy with BCNU, loaded on the polymer, was 50% higher than average survival of patients, receiving placebo (implantation of the polymer alone) [14]. The above research allowed the authors to come to a conclusion, that the method of local chemotherapy of cerebral HGG was effective.

However, it should be noted, that BCNU has a considerable shortcoming. A mechanism of its antineoplastic effect lies in formation of an active metabolite within the liver. It is this very metabolite, which has a direct cytostatic effect. It is known as 2-chlorethylizocyanate [35]. It has a low molecular weight (<200 daltons) and is characterized by good penetration through the blood-brain barrier. That is why, this cytostatic drug was included into the main schemes of multimodality chemotherapy of cerebral HGG.

Cisplatin does not possess this shortcoming. In comparison with BCNU cisplatin proper (but not its metabolites) has a marked cytostatic effect. It is confirmed by numerous studies of sensitivity of primary cellular cultures of human HGG to this drug, carried out in vitro [39, 41]. In its turn, research in vivo revealed, that CLP has a good antineoplastic effect too [22, 23, 29].

This fact became a prerequisite for a new form of this drug, developed by us, i.e. cisplatin, loaded on the home dissolving 6-carboxycellulose polymer and authorized for use in clinical practice. One more cause was, that available literature contained only two reports on clinical use of intratumor chemotherapy with cisplatin in recurrences of malignant cerebral gliomas [11, 24].

One more and not less important cause of cisplatin wide use in multimodality treatment of HGG is a radio-sensitizing effect of this cytostatic drug [18, 38]. Taking into account this fact, we worked out the protocol, in which one of the main criteria of selecting patients for our clinical study was presence of a primary tumor. It allowed to choose an adequate subsequent course of radiotherapy. It should be emphasized, that a radio-sensitizing effect of cisplatin, which manifested itself in radionecrosis of tissue in a tumor perifocal area, was watched by us in two cases (patients N 7 and 10, table 2). Implantation of CLP into walls of a postoperative cyst in these patients was followed by radiotherapy because of a suspected prolonged growth of neoplasm (CT examination of the brain showed presence of tissue with pathologic density near the postoperative cyst). Repeated operation, performed 3 months later, revealed minor necrosis of brain tissue of the postoperative cyst walls; it was confirmed by morphologic examination.

Cisplatin use for systemic polychemotherapy of HGG is considerably limited by its high molecular weight, equal to 300 daltons (only chemical compounds with a molecular weight of 200 daltons are capable of penetrating through the blood-brain barrier) [17, 33]. Thompson S.W. et al. (1984) [40] found out, that cisplatin concentration in brain tissue after its intravenous administration in vivo in a maximum tolerance dose was only 7 mg/kg; it was absolutely insufficient for an antineoplastic effect. Intra-arterial chemotherapy of malignant cerebral tumors with cisplatin (infusion of the drug into a carotid artery) resulted in development of serious complications (retinopathy, irreversible hypoacusis with possible subsequent development of deafness) in 15-20% of cases [43].

Local chemotherapy with cisplatin, loaded on the dissolving 6-carboxycellulose polymer and used by us, did not cause any complications on the part of the CNS and other systems of the human body. Thus, it proves its safety.

Summarizing the experience, existing in the world, and obtained data, we would like to put a special emphasis on the fact, that treatment of cerebral HGG is so far an unsolved problem. In our opinion, the research results are reassuring to some extent and can be used in further development of new methods of multimodality treatment of this disease.

Conclusion

The analysis of the results of local chemotherapy with CLP, used in multimodality treatment of patients with HGG, shows its efficacy on the one hand and absence of marked toxic manifestations on the other. The obtained data prove possibility of its effective application in multimodality treatment of such cases.

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